Effects of nonylphenol on the calcium signal and catecholamine secretion coupled with nicotinic acetylcholine receptors in bovine adrenal chromaffin cells

Nonylphenol (NP) is the most critical metabolite of alkylphenol polyethoxylate detergents. NP is known as an endocrine disruptor with estrogenic activities and as an inhibitor of endoplasmic reticulum Ca2+-ATPase. Estrogen has modulatory roles on ligand-gated ion channels, such as nicotinic acetylcholine receptors (nAChRs). Ca2+-ATPase inhibitors can modulate the cytosolic calcium concentration ([Ca2+]c]) and thus can affect the calcium signaling coupled with nAChRs. Therefore, NP is predicted to have complex effects on the Ca2+ signaling and secretion coupled with nAChRs. This study investigated these effects using bovine adrenal chromaffin cells. The results show that NP suppressed the Ca2+ signaling coupled with nAChRs and voltage-operated Ca2+ channels in a dose-dependent manner, with IC50s of 1 and 5.9 μM, respectively. Estradiol exhibits similar suppression but much lower inhibitory potencies. NP alone induced a transient rise in [Ca2+]c in the presence or absence of extracellular calcium. Thapsigargin, an endoplasmic reticulum Ca2+-ATPase inhibitor, partially suppressed the [Ca2+]c rise induced by NP, but NP totally blocked the [Ca2+]c rise induced by thapsigargin. This illustrates that NP can cause Ca2+ release from thapsigargin-insensitive pools. Thapsigargin suppressed the Ca2+ signaling coupled with nAChRs but increased that coupled with voltage-operated Ca2+ channels. We propose that three routes are responsible for the effects of NP on nAChRs: named receptor channels, voltage-gated Ca2+ channels, and Ca2+-induced Ca2+ release. Three routes are related to the characteristics of NP as steroid-like compounds and Ca2+-ATPase inhibitor.